1. Field of the Invention
The present invention is in the field of antineoplastic compositions and methods.
2. Description of the Background Art
Taurolidine (Bis-(1,1-dioxoperhydro-1,2,4-thiadiazinyl-4)methane) was developed by Geistlich Pharma. It is a white crystalline substance, water soluble up to 2%. It is made up of two molecules of taurinamid and three molecules formaldehyde forming a two-ringed structure bridged by a methylene group.
Taurolidine has primarily an antibiotic and anti-endotoxin effect. It acts by a chemical reaction, so no microorganism resistance has been observed as yet. This effect of taurolidine is mediated by its active metabolites, which are donators of active methylol-groups: Methylol-Taurultam and Methylol-Taurinamide. The active methylol groups inactivate by reacting with the cell wall of bacteria and with the primary amino groups of endotoxins.
Additional effects of taurolidine were reported in the past: inhibition of TNF and IL-1 Beta in mononuclear cells (Bedrosian 1991), inhibition of Tumor Necrosis Factor Toxicity, and inhibition of Peritoneal Tumor Cell Growth in Laparoscopic Surgery (Jacobi 1997).
Taurolidine solutions have been used as instillation or rinsing solutions of the abdominal cavity in cases of peritonitis. In post-operative instillations, conscious patients have reported as a side-effect irritation and sometimes burning sensations.
Monson et al. PCT International Publication Number WO 92/00743 discloses a selective direct inhibiting effect of Taurolidine and/or Taurultam on certain body tumors. (Monson J R T, Ramsey P S, Donohue J H. Preliminary evidence that taurolidine is anti-neoplastic as well as anti-endotoxin and anti-microbial. Abstract. Br J Surg 77(6) 1990, A711) on B16 melanoma cells and Meth A sarcoma cells in a mice model in vivo, and on fibroblastic tumor cells, LS174T (colon-) carcinoma cells and Jurkat (leukemic-) cells in vitro (International Patent PCT No. PCT/EP91/01269, International Publication Number WO 92/00743 PCT “Use of Taurolidine and/or Taurultam for the treatment of tumors”).
In systemic chemotherapy, the antineoplastic agent is unspecifically distributed throughout the body via circulation. Proliferating cells in healthy organs are thus exposed to the same concentrations of the agent as tumor cells. Moreover, intratumoral distribution of the agent may be prevented by different hemodynamic factors in the tumor. The antineoplastic action of most chemotherapeutic agents depends on the different in proliferation rates between normal cells and tumor cells. When these rates are the same, dose-limiting adverse events may occur. It is generally assumed that the effectiveness of chemotherapy increases with the concentration of the agent within the tumor and the duration of exposure. On the other hand, systemic administration is limited by the severity of adverse events.
An approach to overcome this problem is to administer chemotherapeutic agents locally relying on diffusion for their distribution. In local therapy, the antineoplastic agent is introduced into the tumor itself or the area around the tumor. The resulting pressure gradient leads to diffusion of the antineoplastic agent into the tumor. This mode of administration not only increases the concentration of the agent within the tumor but also results in much lower concentrations in other tissues compared to systemic administration.
Various materials such as collagen or biodegradable polymers or silicons used in local drug delivery systems. The materials serve as matrices by means of which embedded local cytostatic agents such as BCNU, mitoxantrone, or cisplatin are introduced into the tumor resection cavity. Moreover, silicones have been used for local delivery of antineoplastic agents. Potential problems with this mode of drug administration may arise when the carrier matrix contains components that undergo complete degradation after a very long time only or not at all. Another risk is the uncontrolled distribution of the antitumor agent in the CSF, which moreover, makes it difficult to accurately determine the concentration at the target. The postoperative changes in the shape and size of the tumor resection cavity associated with edema formation may preclude complete filling of the cavity with the drug-carrying wafers. The resulting inhomogeneous distribution of the agent can lead to pronounced local increases in drug concentration that may have toxic effects on adjacent healthy tissue.
Another approach of local tumor treatment is so-called convection-enhanced drug delivery (CEED) in which the drug is infused into the tumor or the surrounding brain. The drug is distributed by convective transport. However, this mode of administration requires placement of a catheter in most cases, which increases the risk of infection and the incidence of postoperative CSF fistula formation. Furthermore, it is better suited in cases of non-resected tumors. It can hardly be applied following tumor resection.
There remains a need in the art for new methods and compositions for treating tumors.